The immune system is capable of producing two types of antigen-specific responses to foreign antigen. Cell-mediated immunity is the term used to refer to effector functions of the immune system mediated by T lymphocytes. Humoral immunity is the term used to refer to production of antigen-specific antibodies by B lymphocytes. It has long been appreciated that the development of humoral immunity against most antigens requires not only antibody-producing B lymphocytes but also the involvement of helper T (hereafter Th) lymphocytes. Mitchison, Eur. J. Immunol., 1:18-25 (1971); Claman and Chaperon, Transplant Rev., 1:92-119 (1969); Katz et al., Proc. Natl. Acad. Sci. USA, 70:2624-2629 (1973); Raff et al., Nature, 226: 1257-1260 (1970). Certain signals, or “help”, are provided by Th cells in response to stimulation by thymus-dependent (hereafter TID) antigens. While some B lymphocyte help is mediated by soluble molecules released by Th cells (for instance lymphokines such as IL-4 and IL-5), activation of B cells also requires a contact-dependent interaction between B cells and Th cells. Hirohata et al., J. Immunol., 140: 3736-3744 (1988); Bartlett et al., J. Immunol., 143: 1745-1754 (1989). This indicates that B cell activation involves an obligatory interaction between cell surface molecules on B cells and Th cells. Such an interaction is further supported by the observation that isolated plasma membranes of activated T cells can provide helper functions necessary for B cell activation. Brian, Proc. Natl. Acad. Sci. USA, 85: 564-568 (1988); Hodgkin et al., J. Immunol., 145: 2025-2034 (1990); Noelle et al., J. Immunol., 146:1118-1124 (1991).
A cell surface molecule, CD40, has been identified on immature and mature B lymphocytes which, when crosslinked by antibodies, induces B cell proliferation. Valle et al., Eur. J. Immunol., 19:1463-1467 (1989); Gordon et al., J. Immunol., 140:1425-1430 (1988); Gruber et al., J. Immunol., 142: 4144-4152 (1989). CD40 has been molecularly cloned and characterized. Stamenkovic et al., EMBO J., 8:1403-1410 (1989). A ligand for CD40, gp39 (also called CD40 ligand or CD40L) has also been molecularly cloned and characterized. Armitage et al., Nature, 357:80-82 (1992); Lederman et al., J. Exp. Med., 175:1091-1101 (1992); Hollenbaugh et al., EMBO J., 11:4313-4319 (1992). The gp39 protein is expressed on activated, but not resting, CD4+ Th cells. Spriggs et al., J. Exp. Med., 176:1543-1550 (1992); Lane et al., Eur. J. Immunol., 22:2573-2578 (1992); Roy et al., J. Immunol., 151: 1-14 (1993). Cells transfected with the gp39 gene and expressing the gp39 protein on their surface can trigger B cell proliferation and, together with other stimulatory signals, can induce antibody production. Armitage et al., Nature, 357:80-82 (1992); Hollenbaugh et al., EMBO J., 11:4313-4319 (1992).
While the induction of a humoral immune response is an important host defense mechanism, in certain situations it would be beneficial to suppress antibody production against a particular antigen. For example, suppression of a humoral response against an allergen could prevent or reduce an allergic response in an individual. Additionally, when a therapeutic antibody is administered, suppressing a humoral response against the antibody could prolong the therapeutic efficacy of the antibody.